Continuous local slow-release of therapeutics for head and neck problems and upper aerodigestive disorders

ABSTRACT

The invention features formulations for the local delivery of therapeutically effective doses of curcumin to treat head and neck disorders and upper aerodigestive disorders. Also disclosed are use of the formulations for delivery of other phytochemicals, or the combination of phytochemicals for the treatment of said disorders. Furthermore, these formulations can be used to deliver the recommended daily allowance of vitamins and/or minerals to children or adults.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit under 35 U.S.C. 119(e) of U.S.Provisional Application No. 61/189,563, filed Aug. 20, 2008, which isincorporated by reference.

BACKGROUND OF THE INVENTION Field of the Invention

This invention relates to novel therapeutic formulations, theirpreparation, and methods of use for treating head, neck, and upperaerodigestive disorders.

State of the Art

Annually there are ˜40,000 new head and neck squamous cell cancers(HNSCC) patients and 13,000 deaths in the US and 500,000 new casesworldwide (SEER 2007) Despite advances in treatment, the overallsurvival rates (˜45%) have not improved significantly over the lastthree decades. Treatment failure in early stage disease is a result ofsecond primary tumors (SPT) and, in advanced stage disease development,of local recurrence and metastasis resulting in morbidity and mortality.As a result of field cancerization, the probability of SPT occurs at aconstant risk of 4-7% per year following initial treatment but can be ashigh as 22% within 5 years with a 5-year survival rate of 25% in thesepatients. Hence there is a need for chemopreventive agents to delay,arrest or reverse carcinogenesis. The entire mucosa exposed to thecarcinogens in tobacco and alcohol have often undergone atypicalchanges. Moderate to severe dysplasia of the oral cavity and larynx isassociated with a well-defined risk of progressing to invasive cancer in33%-44% of patients. Hence, chemoprevention agents can be used asadjuvant therapy to prevent recurrences in HNSCC which occur in 2-3years. One agent which appears to have promising potential in preventionof tumor progression is curcumin. Curcumin has been proposed as achemoprevention agent but has poor bioavailability. Problems withdysphagia or difficulty swallowing occur from the cancer itself and fromresection, mucositis, and xerostomia following chemotherapy and/orradiation therapy making it difficult for patients to swallow largepills which would be the case with curcumin as large doses are needed toovercome poor bioavailability.

Lessons Learned from Previous Studies and the Need for a Novel Agent:

Although preclinical studies have shown >1,000 compounds havechemopreventive properties, very few have made it to clinical trials.Retinoids are the best-studied class with five randomized retinoidtrials conducted to date in premalignant oral lesions, that were shownto prevent recurrence and SPT. Although the trials showed significantresponse rates, dose related mucocutaneous toxicity has been the majoradverse effect encountered in these trials. High relapse rates were alsonoted which indicates the need for prolonged maintenance therapy. Intrials with retinoids for HNSCC patients, although SPTs weresignificantly reduced, there was no change in survival believed to bedue to high toxicity-related drop out in the retinoid arm, highlightingthe importance of thoroughly investigating dietary supplements such ascurcumin for efficacy.

Improvement of Toxicity:

Non-steroidal anti-inflammatory drugs (NSAIDs) have also been widelyinvestigated as chemoprevention agents, due to the anti-angiogenicproperties of these agents in rodent models. A large study on thechemopreventive effects of the COX-2 inhibitor Celebrex® was haltedbecause of increased risk of cardiovascular events and toxicities inpatients. The COX-2 inhibitor Vioxx® is now removed from the market andthe use of the other COX-2 inhibitor, Celebrex®, is markedly limited.There is a focus now to induce tumor cell apoptosis while compensatingfor COX function to increase efficacy and minimize toxicity. Given theneed for a safer agent and the long term use of chemopreventive agents,curcumin has attracted attention due to its antitumor activity andnegligible toxicity in humans and animals.

Curcumin and its Current Problems:

A natural product isolated from turmeric, curcumin has been implicatedas a powerful therapeutic in a variety of human cancers because of itsability to induce apoptosis and is currently undergoing clinical trialsfor colon, skin, pancreatic, and hematologic cancers, although itseffect on HNSCC has been limited for in vivo benefit due to lowgastrointestinal absorption. Studies have shown increasedbioavailability of curcumin when administered in conjunction with theblack pepper extract piperine in both rats and humans (2000% in humanswith a single dose), although the efficacy remains controversial. Thecommercially available combination of curcumin and piperine, Curcumin C3Complex® (Sabinsa Corp. Piscataway, N.J.), is currently being evaluatedin a phase III trial of metastatic colon cancer, with no dose-limitingtoxicity reported in human clinical trials of curcumin up to 10 g/day.

Pharmacologically active levels of curcumin can be achieved incolorectal tissue in patients taking oral curcumin due to prolongedlocal contact. Although data is lacking, it is unlikely thatpharmacologically active concentrations of curcumin can be achieved intissues that are not directly exposed to a local application.Pharmacokinetic studies of curcumin indicate low bioavailability ofcurcumin following oral administration. There has been significantcontroversy with regards to Bioperine® and its role in improving thebioavailability of curcumin. Toxic side effects are inevitable forchemotherapy regimens, but are unacceptable for chemoprevention. Dailydosing of curcumin up to 8 grams daily for four months demonstrated nodose-limiting toxicity, although higher dosing was prohibited due tobulkiness of pills, which would pose a serious problem to head and neckcancer patients post-surgery or during radiation when swallowing isoften impaired.

SUMMARY OF THE INVENTION

The invention features solid formulations and methods for the local andsustained slow-release delivery of therapies in the oral cavity for thetreatment of head and neck disorders or disorders of the upperaerodigestive track.

In one embodiment of the invention, formulations and methods for theadministration of curcumin are provided. Curcumin's poor bioavailabilityand the relatively high concentrations required for efficacy havelimited its use, both of which are issues that can be overcome by theuse of the present invention. By delivering curcumin, or othertherapeutic agents locally, systemic bioavailability is not an issue andlocal concentrations in the mucosa are likely to reach thetherapeutically effective levels. In some aspects, the present inventionaddresses this problem by providing solid formulations and methods forthe delivery of curcumin and other therapeutic agents by absorptionthrough the oral mucosa.

In accordance with one embodiment, this invention provides a solidformulation in the form of a chewing gum to locally delivery curcumin.In another embodiment, provided are lozenges for local and prolongeddelivery of curcumin.

In another embodiment, provided are solid formulations containingcurcumin and other agents such as phytochemicals and/or vitamins andminerals.

These and other embodiments of the invention are further described inthe text and claims that follow.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 represents the plot of growth inhibition of HNCC cells in vivofollowing treatment with the Curcumin C3 Complex®.

FIG. 2 is a western blot of tissue samples from sleep apnea non-cancerpatients (1-4 and 7-10) and cancer patients (5, 6, 11, and 12) tumor (T)and histologically tumor-free margin (M) probed with antibodies againstphospo-Akt (A) or phospho-mTOR (B).

FIG. 3 represents curcumin's effects on NFκB and Akt/mTOR pathways inHNSCC cell lines in vitro (A) and in vivo (B).

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, provided is a solid oral formulation comprising atherapeutically effective amount of curcumin and a pharmaceuticallyacceptable carrier for oral mucosal delivery of said curcumin.

Suitable oral solid formulations include those in the form of chewinggums, lozenges, and candies for administration of curcumin through theoral mucosa. Such solid formulations contain pharmaceutically acceptablecarriers relevant for that particular form, and such carriers will bewell known to one of skill in the art. The formulations may be chewed,sucked, or placed against the buccal cavity or administeredsublingually. The solid formulations may be in any number of shapes.Non-limiting examples include flat sticks or formulations havingcircular, octagonal, or biconvex shapes.

Pharmaceutical acceptable carriers include ingredients such as buffers,flavorings, aroma agents, sweeteners, colorants, preservatives such asantioxidants, softeners, thickening agents, emulsifiers, glidants,lubricants, and mixtures thereof.

One or more buffers may be used to aid in absorption of curcumin throughthe oral mucosa. Preferred buffers are those capable of increasingsaliva pH to about 7 to 12, to about 7 to 11, or to about 7 to 10 duringadministration. Suitable buffers include sodium carbonate, sodiumbicarbonate, calcium carbonate, potassium carbonate, potassiumbicarbonate, sodium potassium dibasic, sodium potassium tribasic,potassium phosphate dibasic, potassium phosphate tribasic, magnesiumhydroxide, potassium hydroxide, aluminum hydroxide, and mixturesthereof. In some aspects, buffers comprise about 0.1 to about 10% orabout 0.1 to about 5% of the solid formulation.

Flavorants and aroma agents include essential oils and natural andsynthetic compounds that mimic the flavors and aromas of fruits.Flavorants include those having a lemon, orange, lime, spearmint,wintergreen, chocolate, cinnamon, vanilla, coffee, or menthol taste.Suitable flavorant amounts include formulations having from about 0.1 to0.5% by weight of the flavorant.

Sweeteners may be natural or artificial sweeteners. Examples ofsweeteners include sucrose, fructose, mannitol, sorbitol, xylitol,powdered sugar, granulated sugar, molasses, saccharin, acesulfame,aspartame, Nutrasweet, Splenda, and mixtures thereof. In some aspects,sweeteners comprise about 0.001 to about 5% or 10% by weight of thesolid formulation. In another aspect the sweetener comprises 0.5% byweight of the formulation.

Suitable colorants include dyes, pigments, and natural food colorsapproved for use as food additives. In some aspects, the colorantscomprise about 0.001% to about 0.05% by weight of the formulation.

The solid formulations may also contain oils and lubricants to aid inthe preparation of the formulation, such as to prevent sticking toequipment and molds. In some aspects the oils comprise up to 1% byweight of the formulation.

The curcumin used in the formulations may be prepared synthetically orpreferably is isolated from natural sources.

In one embodiment, provided is a chewing gum optionally having a coatinglayer, wherein said gum comprises gum base, corn syrup, citric acid,glycerin, and a therapeutically effective amount of curcumin andoptionally a sweetener.

Processes for preparing gum coatings are well known in the art. Thecoatings aid in enhancing taste and/or product stability during storage.Suitable coatings include those having a sweetened candy coating.

Gum base is a non-nutritive masticatory substance. It is an inert andinsoluble non-nutritive product used as a support for the edible andsoluble portion of the chewing gum (sweetener, glucose, flavors etc).The general description “gum base” used on chewing gum productsthroughout the world is recognized by The Food Chemicals Codex and mostnational legislation. Gum base is produced through a blend of rawmaterials which can be categorized in five classes: 1) elastomers; 2)resins to act as binders and softeners; 3) plasticizers to render theelastomer soft to ensure thorough blending of the gum base; 4) fillersto contribute to the overall texture; and 5) antioxidants to preventoxidation of the gum base and flavors during shelf life. Suitable gumbases include natural and synthetic gum bases. Synthetic gum bases maycontain a mixture of elastomers, plasticizers, fillers, softeners,emulsifiers, and waxes. Examples of gum bases include agar, alginate,arabic gum, carob gum, carrageenan, ghatti gum, guar gum, karaya gum,pectin, tragacanth gum, locust beam gum, gellan gum, and xantham gum.The gum base may comprise 10 to 80% by weight of the chewing gum,excluding the weight of any coating layer.

In some embodiments, the amount of curcumin in each piece of gum isbetween 1 and 500 mg. In other aspects, the amount of curcumin is 350mg.

In other embodiments the gum base is between 0.5 and 2 g. In otheraspects, the amount of gum base is 1.1 g.

In one embodiment, the solid formulation contains sweeteners selectedfrom the group consisting of powdered sugar, granulated sugar, molasses,aspartame, Nutrasweet, and Splenda. In one aspect, the solid formulationcontains between 0 and 2 g of sweetener.

In another embodiment, provided is a chewing gum having between 0.05 and0.5 mL corn syrup for each piece of chewing gum. In some aspects, thechewing gum has 0.18 mL of corn syrup.

In another embodiment, provided is a chewing gum having between 5 mg and25 mg of citric acid. In some aspects, the chewing gum has 12 mg ofcitric acid.

In another embodiment, provided is a chewing gum having between 0.01 and1 mL glycerin. In some aspects, the chewing gum has 0.03 mL of glycerin.

In one embodiment, provided is a method for folding therapies into achewing gum which upon chewing will be slowly released in the oralcavity such that up to 350 mg of the therapeutic can be solubilized (orwet), levigated and folded into a single piece of gum.

In the foregoing method, other phytochemicals, including, but notlimited to EGCG (green tea polyphenol epigallocatechin-3-gallate),resveratrol, piperine, genistein, lycopene, lutein, perillyl alcohol,alpha-carotene, saponins, terpeneol, terpene limonoids, hesperetin,silymarin, tangeretin, ferulic acid, sulforaphene, and capsaicin canalso be folded into the chewing gum as can other nutritional substances,including, but not limited to vitamins such as vitamin B, vitamin C,vitamin D, and vitamin E and minerals such as iron, calcium andpotassium, and other nutritional supplements.

In one aspect, up to 375 mg of curcumin and other phytochemical ornutritional supplement is folded into the chewing gum. In other aspects,the amount of phytochemical is between 1 and 500 mg or is 350 mg.

In another aspect of the invention, phytochemicals, including, but notlimited to curcumin, EGCG, resveratrol, piperine, genistein, lycopene,lutein, perillyl alcohol, alpha-carotene, saponins, terpeneol, terpenelimonoids, hesperetin, silymarin, tangeretin, ferulic acid,sulforaphene, and capsaicin can be delivered to the oral cavity in theform of a spray or paste, as can other nutritional substances,including, but not limited to vitamins, such as vitamin B, vitamin C,vitamin D, and vitamin E, minerals, such as iron, calcium and potassium,and other nutritional supplements.

In the foregoing method, the paste would consist of up to the maximallysoluble amount of the phytochemical or nutritional substance (to make100 gm):

Polyox ® WSR-301 5 gm Pectin USP 2 gm Xanthan Gum 1 gm Gelatin 2 gmAcacia NF 2 gm Carboxymethylcellulose (Medium Viscosity) 4 gm Vaseline(petroleum jelly) 84 gm

Said paste should remain in the oral cavity for at least 10 minutes.

In one embodiment, provided are lozenges containing between 500 and 800mg of curcumin. The lozenge may also contain one or more sweeteners andcontain one or more buffers to facilitate transmucosal curcuminabsorption.

In one embodiment, curcumin is present in the solid formulation as anano-particle. Such particles may be formed according to the generalmethods disclosed in U.S. Pat. No. 5,145,684. In an illustrativeexample, curcumin is pulverized to nanoparticles in the presence of asurface modifier.

In the another embodiment of this invention, other phytochemicals,including but not limited to, EGCG, resveratrol, piperine, genistein,lycopene, lutein, perillyl alcohol, alpha-carotene, saponins, terpeneol,terpene limonoids, hesperetin, silymarin, tangeretin, ferulic acid,sulforaphene, and capsaicin can be used in the foregoing compositions attherapeutically effective concentrations. The phytochemicals can be usedalone or in combinations of two or more, such that the combination doesnot exceed 25-60% (w/w) by weight of the solid formulation.

In other embodiments, the solid formulations further comprise Polyox®WSR-301, Pectin USP, Xanthan Gum, Gelatin, Acacia NF,Carboxymethylcellulose (Medium Viscosity), Vaseline (petroleum jelly)and curcumin or another phytochemical.

In other embodiments, the solid formulations further comprise Methocel®2% gel and optionally another phytochemical.

In some aspects, the amount of curcumin or of another phytochemical isfrom 1 mg to the maximally soluble amount of curcumin or otherphytochemical.

In another aspect, the invention features the use of the foregoingcomposition(s) to treat head and neck cancers. The foregoingcomposition(s) can also be used to treat or prevent other problems ofthe head and neck and upper aerodigestive disorders.

In still another aspect of the invention, the foregoing compositions canbe used as a prophylactic to deliver nutritional supplements. In oneembodiment of the invention, vitamins and/or minerals can be folded intothe chewing gum such that the daily requirement of the vitamins and/orminerals is achieved in a patient by chewing one or more pieces of gumeach day.

By “chemopreventative” is meant a compound that is capable of preventingthe growth or re-growth of a tumor.

By “chewing gum” is meant a sweetened and flavored preparation forchewing.

By “formulation” is meant adding the therapeutic or chemopreventivecompound to an acceptable carrier to facilitate delivery of thecompound.

By “local delivery” or “local application” is meant delivering atherapeutically effective amount of the drug at the site of the disease,problem or disorder.

By “nutritional intervention” is meant use of a dietary supplement forimproving health and reducing the risk of chronic disease or condition.

By “patient” is meant a mammal such as a human.

By “phytochemical” is meant non-nutritive plant chemicals that haveprotective or disease preventive properties.

By “proliferative disease” is meant a disease that is caused by orresults in inappropriately high levels of cell division, inappropriatelylow levels of apoptosis, or both. For example, cancers such as lymphoma,leukemia, melanoma, ovarian cancer, breast cancer, pancreatic cancer,bladder cancer, gastric cancer, salivary gland carcinoma, head and neckcancer and lung cancer are all examples of proliferative disease. Amyeloproliferative disease is another example of a proliferativedisease.

By “therapeutically effective amount” is meant an amount of a compoundsufficient to produce a preventative, healing, curative, stabilizing, orameliorative effect in the treatment of a condition, e.g., aproliferative disease.

By “treating” is meant the medical management of a subject, e.g. ananimal or human, with the intent that a prevention, cure, stabilization,or amelioration of the symptoms or condition will result. This termincludes active treatment, that is, treatment directed specificallytoward improvement of the disorder; palliative treatment, that is,treatment designed for the relief of symptoms rather than the curing ofthe disorder; preventive treatment, that is, treatment directed toprevention of disorder; and supportive treatment, that is, treatmentemployed to supplement another specific therapy directed toward theimprovement of the disorder. The term “treatment” also includessymptomatic treatment, that is, treatment directed toward constitutionalsymptoms of the disorder. “Treating” a condition with the compounds ofthe invention involves administering such a compound, alone or incombination and by any appropriate means, to an animal, cell, lysate orextract derived from a cell, or a molecule derived from a cell.

Head and neck cancer patients carry a higher risk of developing secondprimaries, regardless of their initial treatment modality. Theoccurrence of a subsequent lesion in the entire respiratory and upperaerodigestive tract (UADT) is an important factor for mortality inHNSCC. An agent that can be used to treat HNSCC could be used for otherUADT malignancies such as lung and esophagus. For example, squamous cellcarcinoma (SCC) is a serious problem due to a prevalence of oral tobaccouse and alcohol consumption, especially in the minority population.

Previous studies evaluating the effect of curcumin on TPA-induced(12-0-tetradecanoylphorbol-13-acetate) tumor promotion on mouse skindemonstrated that topical application of 10 μmol curcumin twice weeklyinhibited the number of tumors per mouse by 98% (Huang M, Smart R, etal., 1988; Inhibitory effect of curcumin, chlorogenic acid, caffeicacid, and ferulic acid on tumor promotion in mouse skin by12-O-tetradecanoylphorbol-13-acetate; Cancer Res 48(21):5941-6).Although tumors that develop in the hamster cheek pouch do nothistologically or grossly resemble human oral carcinoma, topicalapplication of 10 μmol curcumin to the cheek pouch of hamsters reducedthe number of DMBA-induced (7,12-dimethylbenz(a)anthracene) oral tumorsby ˜40% when 10 μmol curcumin was applied topically 3 times/week for 24weeks (Li N, Chen X, et al. 2002; Inhibition of7,12-dimethylbenz[a]anthracene (DMBA)-induced oral carcinogenesis inhamsters by tea and curcumin; Carcinogenesis 23(8):1307-13). In a morerecent study (Li M, Zhang Z, et al. 2007; Curcumin, a dietary component,has anticancer, chemosensitization, and radiosensitization effects bydown-regulating the MDM2 oncogene through the PI3K/mTOR/ETS2 pathway;Cancer Res 67(5):1988-96), when curcumin was given by p.o. gavage atdoses of 5 mg/day, 5 days/week for 4 weeks to tumor-bearing nude mice,curcumin inhibited growth of prostate cancer xenograft by ˜50%. To date,a variety of animal models have addressed the chemopreventive propertiesof curcumin in colon or skin cancer.

HNSCC Cell Lines Screened for Sensitivity to Curcumin

Our in vitro data with a variety of HNSCC cell lines has consistentlydemonstrated sensitivity of SCC cells to curcumin with consistentinhibition of cell proliferation at less than 10 M curcumin while ahigher dose of 20-40 μM was required to see effects in a normalfibroblast cell line CCL110 (FIG. 1). These results suggest thepossibility of a favorable therapeutic window in vivo. It is strikingthat a variety of cell lines display a wide range of sensitivity to mTORinhibitors, including rapamycin (sirolimus) and RAD001 (everolimus),whereas a variety of cell lines are consistently sensitive to curcuminwithin a narrow range at physiologically relevant concentrations.

Akt/mTOR Pathway is Activated in HNSCC and Margins Showing PrecancerousChanges

Surgical excision of cancer with a curative intent is guided byobtaining histologically tumor-free margins. Most markers lack thesensitivity and ease of applicability for consistent clinical use. In aprospective study on surgical margins of HNSCC patients, we identifiedeIF4E as the first marker that is elevated in almost all tumor samples,which makes it a sensitive and readily detectable tumor marker inmucosal surgical margins. A total of 276 histologically tumor-free,mucosal surgical margins with a broad range of dysplasia (average of4.25 margins per patient) from 65 patients were analyzed. Expression ofeIF4E has also been shown to correlate with progressive celltransformation in the process of tumorigenesis. We further evaluated thepotential of eIF4E downstream of the mTOR pathway as a biomarker byevaluating its expression in the oral cavity where chronic inflammationis a common occurrence. We then determined that over-expression of eIF4Ein these margins is functionally active via activation of the Akt/mTORpathway and also showed that molecular inhibitors of this pathway suchas CCI-779, a rapamycin analogue, can inhibit tumor formation andimprove survival in a model of minimal residual disease. Thispreferential activation of the Akt/mTOR pathway in our tumor-freemargins compared with the tumor itself could be useful in the design ofclinical trials with mTOR inhibitors, such as curcumin.

The Akt/mTOR Pathway as Biomarkers in Carcinogenesis

We have developed significant data to demonstrate that various parts ofthe Akt/mTOR pathway can serve as adequate biomarkers. Lippman proposedfour criteria for biomarkers in tobacco related epithelialcarcinogenesis and our data demonstrates that Akt/mTOR meet theserequirements. Criteria #1) Biomarker expression in normal tissue shouldbe different from that in high risk tissue. In FIG. 2 we present ananalysis of cancer (lanes 5, 6, 11, and 12) and non-cancer (patientswith sleep apnea) (lanes 1-4 and 7-10) patient samples. The cancersamples include tumors (T) and histologically tumor-free margins (M). Noexpression of pAkt was seen in mucosa of non-cancer patients whiletumors and some margins express pAkt (FIG. 2). Similarly phospho-mTOR(p-mTOR) levels were significantly lower in non-cancer patients comparedto cancer patients. Criteria #2) Biomarkers can be detected in smalltissue specimens. In our studies we have successfully detected bywestern blots and even by IHC the various Akt/mTOR markers on samplesoften as small as 5 mm. Criteria #3) Biomarkers can be expressed in aquantity or pattern that can be correlated with the stage ofcarcinogenesis. We have successfully demonstrated such correlation inour study on precancerous tissue of the head and neck (Nathan C,Franklin S, et al. 1999; Expression of eIF4E during head and necktumorigenesis: possible role in angiogenesis; Laryngoscope109(8):1253-8). Criteria #4) Preclinical or early clinical data indicatethat the condition represented by a marker can be modulated by studyagents. We now also have exciting data indicating modulation of the mTORpathway markers with an mTOR inhibitor not only in preclinical modelsbut having completed our Phase 2 biomarker exploratory trial withtemsirolimus (CCI-779), a rapamycin analogue, we show modulation ofthese markers in tumors and PBMCs (a potential surrogate marker) ofHNSCC patients (Nathan C, Mills G, et al. 2007; An exploratory biomarkertrial of an mTOR inhibitor in subjects with newly diagnosed advancedstage HNSCC; Proceedings AACR Supplement 48:42).

Mechanism of Antitumor Effects of Curcumin

A preliminary microarray analysis of gene expression profiles was usedto characterize mechanisms of inhibition of cell proliferation in HNSCCexposed to 10 μM curcumin for 24-48 hours. Expression of many genes wasmodulated by curcumin, but two prominently affected pathways of interestwere Akt/mTOR and NFκB. These results are the impetus to investigate indetail curcumin's effects on expression levels of genes in these twopathways.

The effects of curcumin on modulation of the NFκB and Akt/mTOR pathwayswere studied in 3 HNSCC and one normal fibroblast (CCL110) cell lineafter exposure to 10 μM of curcumin for 24 and 48 hours (FIG. 3A). Noteall HNSCC cell lines showed inhibition of cell proliferation at 10 μM ofcurcumin (FIG. 1). Three HNSCC cell lines were treated with 10 μmcurcumin for 24 and 48 hours and effects on the NFκB and Akt/mTORpathway were analyzed. FIG. 3 shows that in PCI15a cells, although nochange was noted in pNFκB, both pAkt and pS6 downstream of mTOR weredown-regulated at 48 hours. On the contrary, SCC40 cells showeddown-regulation of pNFκB after 48 hours and no change in the Akt/mTORpathway. Finally SCC066 did not express pNFκB and did not show anymodulation of the Akt/mTOR pathway. The normal fibroblast cell lineCCL110 consistently showed no decrease in any of the pathways testedi.e. pNFκB or Akt/mTOR. It is interesting that although modulation ofthe biomarkers seems so variable in these cell lines all three HNSCCcell lines consistently showed significant growth inhibitory effectswith curcumin at 48 hours. When mice with SCC40 xenografts were treatedwith curcumin there was a significant decrease in pAkt and pS6 (FIG. 3BLanes 3 and 4) although this same cell line in vitro showed no decreasein the phosphorylation status of the Akt/mTOR pathway. The above dataindicates: 1) a panel of biomarkers may be needed in nutritionalintervention studies with curcumin as it appears to affect multiplepathways; 2) Although growth inhibitory in SCC40 cell culture, curcumindid not appear to down-regulate Akt/mTOR in cell culture, yetdown-regulated the pathway in vivo. Hence the need for human clinicaltrials to validate biomarkers with nutritional intervention of safecompounds such as curcumin is important prior to embarking on largescale nutritional intervention studies with this bioactive foodcompound.

Given the above preliminary data it appears that although curcuminappears to have growth inhibitory effects on all 10 HNSCC cell linestested to date, multiple pathways are inhibited. While curcumin can beused to treat these cancers, other compounds that act on these pathwaysmay also be useful in treating these cancers and it should be readilyrecognized that such compounds could also be delivered by including inthe formulations described herein.

Chemoprevention Model Updates

Balb/c nu/nu mice were randomized into treatment groups. In this set ofexperiments, we pre-treated mice with vehicle or higher doses ofcurcumin (10 or 15 mg) for 4 days prior to injecting tumor cells (Day0). Tumors were measured over approximately three weeks. There was astatistically significant difference in tumor volumes between control(vehicle treated) and the 15 mg treated group of mice (p=0.007) by mixed[repeated] ANOVA analysis. However no significant difference was notedat 10 mg of curcumin indicating the importance that high doses may berequired to overcome bioavailability. It was previously shown thatcurcumin has growth inhibitory effects in nude mice with establishedtumors and that the effects of curcumin were significant in the earlystage of tumor development and not the later stages indicatingcurcumin's potential role as a chemopreventive agent or as adjuvanttherapy to prevent recurrence. We show here the growth inhibitoryeffects of curcumin in the early stages of tumor development as expectedwith a cytostatic agent. This also points to its role as achemopreventive agent rather than a therapeutic agent.

Accordingly, the invention provides methods of preventing and treatinghead and neck cancer using curcumin as a nutritional intervention orchemopreventative in patients following treatment of the primary tumor.Given the safety profile of curcumin and nutritional substances, such asvitamins, the solid formulations described can also be used as aprophylactic to prevent the occurrences of diseases or problems.

Formulations of Curcumin

Non-limiting illustrative examples of curcumin formulations aredescribed below. In addition to the listed ingredients, any flavoringcan be added.

In this example, spearmint oil is used as flavoring. To produce a pieceof gum in a troche, the following ingredients are used:

Curcumin: 0.3 g

Gum Base: 1.098 gm

Powdered Sugar: 1.645 gm

Corn Syrup: 0.181 mL

Glycerin: 0.03 mL

Citric Acid USP monohydrate: 0.012 g

The gum is prepared according to the following procedure:

1. Add gum base, citric acid, glycerin and corn syrup in a beaker. In asecond beaker bring enough water to boil to allow a double boilersystem. Melt the mixture of gum base ingredients until gooey. May useglass beadlet for bottom of second water beaker.

2. Measure amount of curcumin necessary to make required number oftroches. Make a well to pour the melted gum base into on a clean pilltile.

3. Add flavor to the melted gum base and reheat if necessary to insuregooey texture. Pour the melted gum base into the center of the well ofcurcumin well and knead the two ingredients together using principles ofgeometric dilution.

4. Mix as fast as possible but with substantial kneading. Kneading toolittle will cause the gum to break up when chewed. Add to troche moldthat is sprayed with Pam and standing by.

5. Remove from troche mold after about 20 minutes. May optionallydispense in a pill bottle.

Alternatively, it may be possible to use glycerin in step 2 and “wet”the curcumin to allow for increased dosage and better mixing.

The following is an example of a lozenge containing curcumin:

Curcumin: 0.3 g

Mannitol: 0.2 g

Xylitol: 1.3 g

Sodium carbonate: 0.5 g

Sodium bicarbonate: 0.15 g

Magnesium stearate: 0.01 g

Hydrogenated vegetable oil: 0.025 g

The curcumin in dispersed in mannitol and the powders are mixed. Themixture is next compressed using a tablet press.

While the above examples describe the use of curcumin as the activeingredient, it should be obvious that any therapeutically effectivecompound, nutritional intervention or chemopreventative could also beformulated and delivered in a similar manner for the treatment of headand neck problems and upper aerodigestive disorders. Similarly, theabove delivery strategies could be used to deliver nutrients, such asvitamins and minerals.

Synergistic Effects of Compounds with Other Compounds

While curcumin has been shown to be effective on its own in treatinghead and neck cancer and a variety of other disorders, phytochemicals orother therapies with different mechanisms of action, when combined withcurcumin could result in even more robust effects. For example, curcuminis known to act on the Akt/mTOR pathway as described herein, whereasanother phytochemical, EGCG, has been demonstrated to act at least inpart on the c-met signaling pathway. Thus, the combination of these twocompounds may result in more efficacious treatments. Similar, it shouldbe readily apparent that other compounds acting on pathways outside theAkt/mTOR pathway could be combined and used as treatments in theformulations described herein.

Delivery of Nutrients

The formulations described in this invention, particularly the chewinggum, can also be used to delivery other nutrients, such as vitamins andminerals. While these are typically taken as one-a-day tablets orcapsules, their incorporation and release from a chewing gum couldincrease compliance in children and some adults. A combination ofvitamins and minerals could, therefore, be formulated in one or morepieces of gum such that the total would provide the FDA recommendeddaily allowance.

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each independent publication or patent application was specificallyand individually indicated to be incorporated by reference.

While the invention has been described in connection with specificembodiments thereof, it will be understood that it is capable of furthermodifications and this application is intended to cover any variations,uses, or adaptations of the invention following, in general, theprinciples of the invention and including such departures from thepresent disclosure that come within known or customary practice withinthe art to which the invention pertains and may be applied to theessential features hereinbefore set forth, and follows in the scope ofthe claims.

1. (canceled)
 2. A method of treating one of a cancer and a pre-cancerstate in a mammal comprising: administering to the mammal a solid oralformulation in the form of a lozenge or a chewing gum, the oralformulation comprising a therapeutically effective amount of atherapeutic and a pharmaceutically acceptable carrier for oral mucosaldelivery of the therapeutic, wherein the therapeutic includes a firstphytochemical and the first phytochemical is curcumin, and thetherapeutic is absorbed by the mammal via mucosal absorption.
 3. Themethod of claim 2 wherein the therapeutic further comprises a secondphytochemical which is not curcumin.
 4. The method of claim 3 whereinthe first phytochemical and the second phytochemical have differentmechanisms of action.
 5. The method of claim 3 wherein the secondphytochemical are selected from the group consisting of EGCG,resveratrol, piperine, genistein, lycopene, lutein, perillyl alcohol,alpha-carotene, saponins, terpeneol, terpene limonoids, hesperetin,silymarin, tangeretin, ferulic acid, sulforaphene, and capsaicin.
 6. Themethod of claim 2 further comprising the step of the solid oralformulation eluting curcumin in an oral cavity of the mammal at aconcentration of substantially 10 μM.
 7. The method of claim 6 furthercomprising administering sufficient solid oral formulations to themammal such that curcumin is eluted into the oral cavity for a totalperiod of more than 24 hours.
 8. The method of claim 6 furthercomprising administering sufficient solid oral formulations to themammal such that curcumin is eluted into the oral cavity for a totalperiod of less than 48 hours.
 9. The method of claim 6 furthercomprising administering sufficient solid oral formulations to themammal such that curcumin is eluted into the oral cavity for a totalperiod of between 24 and 48 hours.
 10. The method of claim 2 furthercomprising the step of eluting curcumin from the solid oral formulationinto the mammals oral cavity for sufficient time at a sufficientconcentration to inhibit growth of squamous cell cancer cells.
 11. Themethod of claim 2 further comprising the step of eluting curcumin fromthe solid oral formulation into the mammals oral cavity for sufficienttime at a sufficient concentration to down-regulate Akt/mTOR in squamouscell cancer cells.
 12. The method of claim 2 wherein the solid oralformulation is in the form of chewing gum including a gum base.
 13. Themethod of claim 12 wherein therapeutic elutes curcumin at aconcentration of 10 μM when chewed; the carrier includes a sweetener, aflavorant, and a buffer; the sweetener includes one of sucrose,fructose, mannitol, sorbitol, xylitol, powdered sugar, granulated sugar,molasses, saccharin, acesulfame, aspartame, Nutrasweet, Splenda, andmixtures thereof, and the sweetener comprises about 0.001 to about 10%by weight of the solid formulation; and the buffer is capable ofincreasing saliva pH to about 7 to 12 during administration, the buffercomprises about 0.1 to about 10% of the solid formulation, and thebuffer is one of sodium carbonate, sodium bicarbonate, calciumcarbonate, potassium carbonate, potassium bicarbonate, sodium potassiumdibasic, sodium potassium tribasic, potassium phosphate dibasic,potassium phosphate tribasic, magnesium hydroxide, potassium hydroxide,aluminum hydroxide, and mixtures thereof.
 14. The method of claim 2wherein the solid oral formulation is in the form of a lozenge thatdissolves after an extended time exposed to saliva in an oral cavity ofthe mammal.
 15. The method of claim 14 wherein the therapeutic elutescurcumin at a concentration of 10 M when exposed to saliva in an oralcavity of the mammal; the carrier includes a sweetener, a flavorant, anda buffer; the sweetener includes one of sucrose, fructose, mannitol,sorbitol, xylitol, powdered sugar, granulated sugar, molasses,saccharin, acesulfame, aspartame, Nutrasweet, Splenda, and mixturesthereof, and the sweetener comprises about 0.001 to about 10% by weightof the solid formulation; and the buffer is capable of increasing salivapH to about 7 to 12 during administration, the buffer comprises about0.1 to about 10% of the solid formulation, and the buffer is one ofsodium carbonate, sodium bicarbonate, calcium carbonate, potassiumcarbonate, potassium bicarbonate, sodium potassium dibasic, sodiumpotassium tribasic, potassium phosphate dibasic, potassium phosphatetribasic, magnesium hydroxide, potassium hydroxide, aluminum hydroxide,and mixtures thereof.
 16. The method of claim 3 wherein the firstphytochemical and the second phytochemical have different mechanisms ofaction.
 17. The method of claim 3 wherein the second phytochemical isEGCG and an amount of curcumin in each lozenge or piece of gum is one ofbetween 1 and 800 mg and between 350 mg and 500 mg.
 18. The formulationof claim 2 wherein an amount of curcumin in each lozenge or piece of gumis between one of 350 and 800 mg.
 18. The method of claim 2 wherein thecancer or pre-cancer state is one of colon cancer, skin cancer,hematologic cancer, lymphoma, leukemia, melanoma, ovarian cancer, breastcancer, pancreatic cancer, bladder cancer, gastric cancer, salivarygland carcinoma, head and neck cancer and lung cancer or a pre-cancerstate thereof.
 19. A method of treating one of a cancer and a pre-cancerstate in a mammal comprising: administering to the mammal a solid oralformulation comprising a therapeutically effective amount of thetherapeutic and a pharmaceutically acceptable carrier for oral mucosaldelivery of the therapeutic, wherein the therapeutic includes curcumin,the solid oral formulation is in the form of a lozenge or a piece ofgum, the therapeutic is absorbed by the mammal via mucosal absorption,the cancer or pre-cancer state is one of colon cancer, skin cancer,hematologic cancer, lymphoma, leukemia, melanoma, ovarian cancer, breastcancer, pancreatic cancer, bladder cancer, gastric cancer, salivarygland carcinoma, head and neck cancer and lung cancer or a pre-cancerstate thereof; an amount of curcumin in each lozenge or piece of gum isone of between 1 and 800 mg and between 350 mg and 500 mg; the oralformulation elutes curcumin at a concentration of 10 μM when one ofchewed and exposed to saliva in an oral cavity of the mammal; and thecarrier includes a sweetener, a flavorant, and a buffer.